PROJECT SUMMARY Age Related Macular Degeneration (AMD) is the major cause of blindness. The limited therapies available to the majority of AMD sufferers demand additional approaches and more pathophysiologic information that can lead to new drug treatments to prevent or arrest AMD. Encouragingly, recent epidemiologic literature indicates that consuming lower glycemic index (GI) diets (LG) is related to diminished risk for AMD and AMD progression in humans. Of concern, consumption of the typical American high GI diet (HG) is quantitatively associated with higher risk for onset and progress of AMD. Together, the available data indicate that excessive oxidative and glucose-derived damage (collectively called glycative damage) is associated with and is likely causative for AMD. Our published and preliminary data suggest that it may be possible to arrest AMD-related features (AMDf) at an early stage by switching from HG to LG diets. We need masked, randomized clinical studies to prove the GI-AMD relationship, but these are challenging due to insufficient understanding of the pathophysiology of the association, high cost, lack of biomarkers, and long duration required. We will address these voids while also attempting to enhance cellular preservation capacities as a new way to avoid AMDf. In Aim 1, using wildtype mice consuming HG diets to model the excessive glycative damage associated with AMD, we will seek to demonstrate that AMDf is delayed or arrested and visual function is prolonged by moving to lower GI diets. In order to mitigate damage caused by excessive glycative stress, we will also overexpress the glyoxalase gene GLO1 (a major enzyme that detoxifies glycative damage) and test whether it prevents AMDf. In Aim 2, we will use advanced mouse and human (comparative) metabolomic data to identify potential biomarkers of AMDf and reveal pathways and mechanisms of dietary GI-related AMD. These biomarkers will serve as biomarkers, allowing for ?earlier warning? about the need dietary change or therapy. In Aim 3, we will determine how endogenous protective capacities can be exploited in new ways to preserve retinal function. We will use two FDA-approved drugs, acarbose and empagliflozin to diminish glycative stress associated with HG diets. We will also enhance the ubiquitin-proteasome and autophagic degradation systems in order to mitigate accumulation of damaged and glycated cytotoxic proteins or their precursors, thereby diminishing risk for AMDf. Together, this research will contribute to improved understanding of- and therapy for- AMD by elucidating the pathobiology of the dietary GI-AMD relationship. By accomplishing these objectives, we will help achieve the NEI retina research program's goal to ?understand the molecular and biochemical bases for different forms of AMD, improve early diagnosis, characterize environmental effects on its etiology, and develop new treatments.? Moreover, since CVD and diabetes are also related to the higher dietary GI of the American diet, the findings will have broad applicability.